The long term goal of this project will continue to be to investigate and determine the specific factors that lead to development of endometrial cancer in postmenopausal women. Our previous studies indicate that postmenopausal women with endometrial cancer have hyperinsulinemia and insulin resistance. First aim of this project is to fully characterize the nature of insulin resistance in postmenopausal women with endometrial cancer. Second aim will be to investigate the effect of insulin on the ovarian stroma. Third aim is to investigate the possible role of insulin on the development and progression of endometrial cancer. Fourth aim is to investigate the role of insulin like growth factors in the growth and development of endometrial cancer. 125I insulin binding in circulating monocytes and other insulin resistance studies has been done as described in the original proposal. More patients will be recruited and studied during the next budget period so that patients and controls will be comparable for age, years since menopause and body weight. The effect of aging and years of menopause on insulin resistance is also being investigated. Studies on growth promoting effect of insulin: The growth promoting effect of insulin on five different endometrial cancer cell lines with different degrees of differentiation were studied. Binding studies with 125I insulin revealed presence of high affinity binding sites for insulin on all the 5 cell lines. The effect of insulin like growth factors I and II was investigated on SKUT-1 cell line derived from a highly malignant mixed mesodermal tumor of the uterus. These results indicate that insulin is mitogenic to endometrial cancer cells in culture. Therefore, increased incidence of endometrial cancer seen in obese women could be related to hyperinsulinemia. Development of measures to reduce insulin levels may help prevent development of endometrial cancer. Mixed mesodermal tumors are highly malignant tumors with poor prognosis. Responsiveness of the mixed mesodermal cells to IGF-II indicate that Suramin, which has been shown to decrease IGF-II levels and inhibit IGF-II binding to cells may be effective in inhibiting growth of these tumors.